CN105579033A - Compression coated pulsatile release composition - Google Patents

Abstract

The present invention is directed to a dosage form comprising an immediate release portion of a first active pharmaceutical ingredient and a delayed release portion of a second active pharmaceutical ingredient wherein (a) the immediate release portion comprises from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; and (b) the delayed release portion comprises from about 1 mg to about 1000 mg of the second active pharmaceutical ingredient; wherein the delayed release portion is coated with a delayed release coating comprising at least one swellable erodible polymer and a filler, and wherein the immediate release portion is in contact with the delayed release coating.

Description

Compression coated pulsatile release composition

Cross References to Related Applications

This application claims priority to the filing benefit of U.S. Provisional Application Serial No. 61/883,590, filed September 27, 2013, and U.S. Provisional Application Serial No. 62/030,310, filed July 29, 2014, each of the aforementioned provisional applications The contents of are hereby incorporated by reference in their entirety.

technical field

The present invention relates to a solid dosage form containing an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is delivered in a pulsatile manner. A method of making the solid dosage form is also provided.

Background technique

Therapeutic agents for the treatment of pain, inflammation and fever include analgesics, anti-inflammatory agents and antipyretics. Non-steroidal anti-inflammatory drugs (NSAIDs) are one type of such therapeutic agents. They include propionic acid derivatives, acetic acid derivatives, fenamic acid derivatives, biphenylcarboxylic acid derivatives, oxicams, and cyclooxygenase-2 (COX-2) selective NSAIDs.

Propionic acid drugs include, for example, ibuprofen, naproxen, and ketoprofen. In particular ibuprofen, which is a well known NSAID with analgesic and antipyretic properties, is widely used. It has been marketed in various forms as an over-the-counter drug for many years. Ibuprofen is chemically known as 2-(4-isobutylphenyl)-propionic acid.

NSAIDs are usually administered one to four times daily in a daily dosage ranging from about 50 to about 2000 mg, preferably from about 100 to 1600 mg, and most preferably from about 200 to about 1200 mg.

Acetaminophen (APAP) is a well known analgesic with a daily dosage ranging from about 325 to about 4000 mg, preferably from about 650 to about 4000 mg. Given the widespread use of APAPs and the volume of their manufacture, their manufacture and their use as analgesics are well known to those skilled in the art.

NSAIDs, acetaminophen, and other drugs are known to be administered in multiple doses over a 12 or 24 hour period. For example, it is known to administer multiple doses containing equal amounts of ibuprofen over 12 to 24 hours. Sustained release dosage forms containing ibuprofen are also known.

It is useful to minimize the "drug exposure time" of the patient. In other words, the least total amount of drug is administered to provide the best beneficial therapeutic effect. In particular, administration of analgesics such as NSAIDs or acetaminophen is useful in regimens that provide maximal analgesic effect at the smallest total daily dose of drug.

Applicants have now created a dosage form that provides a two-step dosing regimen with improved therapeutic efficacy, particularly pain relief.

Contents of the invention

The present invention relates to a dosage form comprising an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, wherein (a) the immediate release portion comprises from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; and (b) The sustained release portion comprises from about 1 mg to about 1000 mg of the second active pharmaceutical ingredient; wherein the sustained release portion is coated with a sustained release coating comprising at least one swellable, erodable polymer and a filler, and wherein the immediate release portion is combined with the sustained release coating clothing contact.

The present invention also includes a method for manufacturing an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, the method comprising: (a) obtaining a composition comprising from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient core; (b) compressing a powder onto the surface of the core to form a sustained release coating on the surface of the core, wherein the powder comprises at least one swellable erodible polymer and a filler; and (c) compressing a second powder onto the sustained release coating. On the surface of the release coating, wherein the second powder contains about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; wherein the immediate release part comprises the compressed second powder, and the sustained release part comprises the core and the sustained release coating.

Description of drawings

The specific implementation will be better understood in conjunction with the accompanying drawings:

Figure 1 shows the dissolution profile of the tablet described in Example 2(d);

Figure 2 shows the dissolution profile of the tablet described in Example 2(e);

Figure 3 shows the dissolution profile of the tablet described in Example 2(f);

Figure 4 shows the dissolution profile of the tablets prepared in Example 8 using compression method A (from Example 8);

Figure 5 shows the dissolution profile of tablets prepared in Example 9, Part A (10% wax) using compression method B (from Example 8) in a compression coat of 1.8X core weight;

Figure 6 shows Example 9, Part A (10% Wax) at 2X core weight for compression coating using compression method A (from Example 8), and at 2X core weight for compression coating using compression method B (from Example 8). 8) Dissolution profile of the tablet prepared in Example 9, part A (10% wax);

Figure 7 shows the dissolution profile of tablets prepared in Example 9, Part A (10% wax) using compression method B (from Example 8) in a compression coat of 2.3X core weight;

Figure 8 shows the dissolution profile of tablets prepared in Example 9, Part A (10% wax) using compression method A (from Example 8) in a compression coat of 2.6X core weight;

Figure 9 shows the dissolution profile of tablets prepared in Example 9, Part B (30% Wax, 15% HPMCK4MCR, 30% HPCEXF) using compression method B (from Example 8) in a compression coat of 2.6X core weight;

Figure 10 shows the dissolution profile of tablets prepared in Example 9, Part C (30% Wax, 13% HPMCK4MCR, 26% HPCEXF) using compression method B (from Example 8) in a compression coat of 2.6X core weight;

Figure 11 shows the dissolution profile of the tablets prepared in Example 9, Part D (60% wax) using compression method B (from Example 8) in a compression coat of 2.6X core weight; and

Figure 12 shows the dissolution profile of the tablets prepared in Example 10 with a 2.6X core weight compression coating.

detailed description

The present invention includes compositions for compression coating, active pharmaceutical ingredient ("API") cores in order to obtain tablet dosage forms with pH independent pulsatile (pulse) release. Pulse release is intended to provide sustained release of the API from about 2 to about 8 hours, preferably from about 2 to about 6 hours, more preferably from about 3 to about 6 hours, and even more preferably from about 4 to about 6 hours after the initial initiation of the dose dose.

In another embodiment, the present invention is directed to a dosage form comprising an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient. The immediate release portion contains from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient, and the extended release portion contains from about 1 mg to about 1000 mg of the second active pharmaceutical ingredient. The sustained release portion is coated with a sustained release coat comprising at least one swellable, erodable polymer, and the immediate release portion is in contact with the sustained release coat.

Solid dosage forms are designed to deliver from about 1 mg to about 1000 mg of the active pharmaceutical ingredient in an immediate release portion. Preferably, the immediate release portion delivers from about 1 mg to about 500 mg, and more preferably from about 1 mg to about 400 mg, of the solid dosage form. Even more preferably, the immediate release portion delivers about 100 mg to about 400 mg, and even more preferably about 150 mg to about 400 mg of the solid dosage form. The dosage form contains a specific amount of active pharmaceutical ingredient, depending on whether one or two tablets are ingested at a specific dosing time. For ease of administration and swallowing, two tablets may be preferred. In one embodiment, the immediate release portion comprises from about 300 mg to about 400 mg of active pharmaceutical ingredient when one tablet is ingested. In another embodiment, the immediate release portion comprises from about 150 to about 200 mg of active pharmaceutical ingredient per tablet when two tablets are ingested at a time.

The sustained release portion of the solid dosage form is designed to contain from about 1 mg to about 1000 mg of active pharmaceutical ingredient. Preferably, the active pharmaceutical ingredient is from about 1 mg to about 500 mg, and more preferably from about 1 mg to about 400 mg. Even more preferably, the active pharmaceutical ingredient is from about 100 mg to about 400 mg, and even more preferably from about 150 mg to about 400 mg. In one embodiment, the sustained release portion contains from about 100 mg to about 300 mg of active pharmaceutical ingredient when one tablet is ingested. In another embodiment, the sustained release portion comprises from about 100 to about 150 mg of active pharmaceutical ingredient per tablet when two tablets are ingested at a time.

The first API and the second API can be any active pharmaceutical ingredients. For example, pain relievers, anti-inflammatory agents, antipyretics, antihistamines, decongestants, antitussives and expectorants, muscle relaxants, stimulants, sedatives, appetite suppressants, narcotics, statins, etc. .

The dosage form of the present invention comprises a first active ingredient and a second active ingredient. The first active ingredient and the second active ingredient may be, for example, acetaminophen, aspirin, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, melopran, rofecoxib, Lecoxib and their pharmaceutically acceptable salts, esters, isomers and mixtures and combinations thereof. Other suitable active ingredients for use in the present invention include: analgesics, anti-inflammatory agents, anti-arthritic agents, anesthetics, antihistamines, antitussives, antibiotics, anti-infectives, antivirals, anticoagulants , antidepressants, antidiabetics, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, Decongestants, oral contraceptives, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, dimethicone, respiratory agents, Sleep aids, urinary tract agents, and mixtures thereof.

Examples of suitable analgesic, anti-inflammatory and antipyretic agents include, but are not limited to: non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (e.g., sodium ibuprofen, ibuprofen, naproxen, ketone Profen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, flurprofen, biprofen, carprofen, promethazine, pranoprofen, and suprofen) and COX inhibitors, such as celecoxib; acetaminophen; acetylsalicylic acid; acetic acid derivatives, such as indomethacin, diclofenac, sulindac, and tolmetin ; fenamic acid derivatives, such as mefenamic acid, meclofenamic acid, and flufenamic acid; biphenylcarboxylic acid derivatives, such as diflunisal and flufensal; and oxicams, such as piroxicam , sudoxicam, isoxicam, and meloxicam; their isomers; and their pharmaceutically acceptable salts and prodrugs.

Examples of antihistamines and decongestants include, but are not limited to, brompheniramine, chlorcyclazine, dexbrompheniramine, bromhexine, phenindamine, pheniramine, mepyramine, sonzila Allergens, pripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofena Ding, naphazoline, oxymetazoline, montelukast, acetidine, phenylpropene, climarine, avastin, promethazine, oxomazine, mequitazine, cloth Crimizine, bromhexine, ketotifen, terfenadine, ebastine, bemizosin, xylorazoline, loratadine, decarboxyloratadine, and cetirizine; their iso conformers; and their pharmaceutically acceptable salts and esters.

Examples of cough suppressants and expectorants include, but are not limited to: diphenhydramine, dextromethorphan, noscapine, clophenedol, menthol, benzonatate, ethylmorphine, codeine, acetylsemi Cystine, carboxymethylcysteine, ambroxol, belladonna alkaloids, sobrisol, guaiacol, and guaiacol; their isomers; and their pharmaceutically acceptable salts and prodrugs.

Examples of muscle relaxants include, but are not limited to: cyclobenzaprine and chlorzoxazone, metaxalone, orphenadrine, and methocarbamol; their isomers; and their pharmaceutically acceptable salts and prodrug.

Examples of stimulants include, but are not limited to: caffeine.

Examples of sedatives include, but are not limited to, sleep aids such as antihistamines (eg, diphenhydramine), eszopiclone, and zolpidem, and their pharmaceutically acceptable salts and prodrugs.

Examples of appetite suppressants include, but are not limited to, phenylpropanolamine, phentermine, and diethylcathinone, and their pharmaceutically acceptable salts and prodrugs.

Examples of anesthetics (eg, for the treatment of sore throat) include, but are not limited to, dyclonine, benzocaine, and pectin, and their pharmaceutically acceptable salts and prodrugs.

Examples of suitable statins include, but are not limited to, atorvastatin, rosuvastatin, fluvastatin, lovastatin, simvastatin, atorvastatin, pravastatin, and pharmaceutically available Accepted salts and prodrugs.

Examples of suitable gastrointestinal agents include: antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, sodium dihydroxyaluminate; stimulant laxatives such as diacetate Pyridine, buckthorn buckthorn, dihydroxyanthraquinone, senna, phenolphthalein, aloe vera, castor oil, ricinoleic acid and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists such as famotidine, radium Nitidine, cimetidine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectants such as sucralfate and misoprostol; gastrointestinal motility prucalopride; antibiotics for H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperidine glycopyrrolate; antiemetics such as ondansetron; analgesics such as mesalamine.

In one embodiment of the present invention, the first active ingredient and/or the second active ingredient may be selected from: pseudoephedrine, phenylephrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine , astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, their mixtures and pharmaceutically acceptable salts, esters, isomers, para Acetaminophen, Nicotine, Ranitidine, Ibuprofen, Ketoprofen, Loperamide, Famotidine, Calcium Carbonate, Simethicone, Methocarbamol, Chlorphenedol, Ascorbic Acid, Fruit gum, dyclonine, benzocaine and methanol, their pharmaceutically acceptable salts and their prodrugs, and mixtures thereof.

In another embodiment, the immediate release portion comprises ibuprofen and its derivatives. In another embodiment, the immediate release portion comprises ibuprofen sodium and the extended release portion comprises ibuprofen. In another embodiment, the immediate release portion comprises sodium ibuprofen and the extended release portion comprises sodium ibuprofen.

The first API and the second API may be the same or different.

In one embodiment, the amount of the first API to the amount of the second API is about 1:1 to about 2:1.

In one embodiment, the API has a solubility greater than about 1 mg/ml. In another embodiment, the API has a solubility greater than about 100 mg/ml. In another embodiment, the API has a solubility greater than about 150 mg/ml. In another embodiment, the API has a solubility greater than about 200 mg/ml. In another embodiment, the API has a solubility greater than about 250 mg/ml. It should be noted that solubility was determined at 25°C.

The coating of the present invention comprises at least one swellable erodible polymer. Suitable swellable, erodible polymers include, but are not limited to, hydroxypropyl cellulose (HPC, HF), hypromellose (HPMCK15M or HPMCK4M), hydroxyethylcellulose, and mixtures thereof. Additional swellable, erodible polymers include, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose (Methocel K100M), hydroxyethylcellulose, and mixtures thereof. In one embodiment, the high molecular weight water soluble polymer comprises hydroxypropyl cellulose having a weight average molecular weight of from about 80,000 to about 1,150,000. In another embodiment, the high molecular weight water soluble polymer comprises hydroxypropylmethylcellulose (e.g., hypromellose) having a viscosity in a 2% aqueous solution at 20°C of about 75 to about 120,000 centipoise .

Other examples of swellable, erodable, hydrophilic materials useful as release-modifying excipients in the preparation of coatings or portions thereof include: water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, Acrylic polymers, hydrocolloids, clays, gelling starches and swellable cross-linked polymers, and their derivatives, copolymers and combinations. Examples of suitable swellable erodible cellulose derivatives include: sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), Hydroxyisopropylcellulose, Hydroxybutylcellulose, Hydroxyphenylcellulose, Hydroxyethylcellulose (HEC), Hydroxypentylcellulose, Hydroxypropylethylcellulose, Hydroxypropylbutylcellulose, Hydroxypropyl ethyl cellulose. Examples of suitable polyalkylene glycols include polyethylene glycols. Examples of suitable thermoplastic polyalkylene oxides include poly(ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylate-divinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high molecular weight crosslinked acrylic acid homopolymer and copolymer), and the like. Examples of suitable hydrocolloids include: alginate, agar, guar gum, locust bean gum, kappa carrageenan, I carrageenan, tara gum, gum arabic, tragacanth, pectin, xanthan Gum, gellan gum, maltodextrin, galactomannan, shiurin, laminarin, sclerotin, gum arabic, inulin, pectin, gelatin, welan gum, rhamna gum, fungus Micelle, methylene blue gum, chitin, cyclodextrin, chitosan.

The swellable erodible polymer is included in the coating in an amount of from about 2% to about 60% by weight of the coating. Preferably, in the solid dosage form, the swellable erodible polymer is from about 2% to about 50%, and more preferably from about 4% to about 40%, by weight of the coating.

In some embodiments, the coating comprises two types of swellable erodible polymers. The first swellable erodible polymer may be from about 1% to about 50% by weight of the coating, preferably from about 10% to about 40% by weight of the coating, more preferably from about 20% to about 35% by weight of the coating exist. The second swellable erodible polymer may be from about 1% to about 20% by weight of the coating, preferably from about 10% to about 20% by weight of the coating, more preferably from about 12% to about 18% by weight of the coating exist. In one embodiment, the first swellable erodible polymer is hydroxypropyl cellulose and the second swellable erodable polymer is hypromellose. In another embodiment, the first swellable erodible polymer is hypromellose and the second swellable erodible polymer is hydroxypropyl cellulose.

In one embodiment, the amount of the first swellable erodible polymer to the amount of the second swellable erodible polymer is from about 1:1 to about 2:1.

Dosage forms also contain fillers. In one embodiment, the coating comprises from about 10% to about 99% by weight of the coating, preferably from about 30% to 99% by weight of the coating, more preferably from about 40% to about 99% by weight of the coating, And even more preferred is from about 40% to about 60% filler by weight of the coating. Non-limiting examples include lactose, microcrystalline cellulose, and mixtures thereof.

Suitable fillers may include water-soluble (eg, carbohydrate) fillers such as lactose, dextrose, sucrose, mannose, mannitol, sorbitol, erythritol, xylitol, or mixtures thereof.

In some embodiments, the filler can be a water insoluble material such as a low melting point hydrophobic material and/or a water insoluble polymer.

Suitable low melting point hydrophobic materials include water insoluble fillers such as fats, fatty acid esters, phospholipids, waxes, vegetable oils, free fatty acids and their salts, phospholipids fats, fatty acid esters, phospholipids and waxes.

Examples of suitable fats include: hydrogenated vegetable oils such as cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include: sucrose fatty acid esters; mono, diglycerides and triglycerides, glyceryl behenate, glyceryl palmitoyl stearate, glyceryl monostearate, glycerol Glyceryl Tristearate, Glyceryl Trilaurate, Glyceryl Myristate, GlycoWax-932, Lauroyl Macrogol-32 Glycerides, and Stearoyl Macrogol-32 Glycerin ester. Examples of suitable phospholipids include: phosphatidylcholine, phosphatidylserine, phosphatidylinositol and phosphatidic acid. Examples of suitable waxes include: carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax, among others.

The coating composition may also contain water insoluble polymers. Examples of suitable water-insoluble polymers include: ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, etc. etc. and their derivatives, copolymers and combinations.

In one embodiment, the coating composition comprises water soluble fillers and water insoluble fillers.

Optionally, other ingredients may be included in the compositions or dosage forms of the invention.

Other ingredients or components may be added to the composition, including but not limited to: superdisintegrants, lubricants, glidants, flavoring agents; sweeteners such as sorbitol, sugar, and high intensity sweeteners such as triclosan Sucrose, aspartame and saccharin, etc. may be included therein.

Any coloring agent suitable for use in food or pharmaceutical products may be used in the compositions or dosage forms of the present invention. Typical colorants include, for example, azo dyes, quinophthalone dyes, triphenylmethane dyes, xanthene dyes, indigo dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof. More specifically, suitable colorants include, but are not limited to, Patent Blue V, Acid Brilliant Green BS, Red 2G, Azorubine, Ponceau 4R, Amaranth, D&C Red 33, D&C Red 22, D&C Red 26, D&C Red 28, D&C Yellow 10, FD&C Yellow 5, FD&C Yellow 6, FD&C Red 3, FD&C Red 40, FD&C Blue 1, FD&C Blue 2, FD&C Green 3, Bright Black BN, Carbon Black, Iron Oxide Black, Iron Oxide Red, Iron oxide yellow, titanium dioxide, riboflavin, carotene, anthocyanin, turmeric, cochineal extract, chlorophyll, canthaxanthin, caramel, betaine and mixtures thereof.

Similarly, flavoring agents may be included in the composition or solid dosage form. The amount of flavoring agent added to the composition will depend on the desired mouthfeel characteristics.

It is an object of the present invention to provide a dosage form with a partial release lag time (delay) of the active ingredient, wherein a minimal amount of the active ingredient is released for a predetermined amount of time (2-8 hours), followed by a burst release of the active ingredient after the lag time. The ingredients are for a short period of time, eg less than 60 minutes, preferably less than 30 minutes. In one embodiment, after a lag time of 6 hours, the active ingredient may exhibit less than 5% release within 6 hours followed by greater than 80% release in an additional 60 minutes (eg, 7.0 hours). Various ratios of these materials will provide varying lag times. Furthermore, coating thickness can affect release rate and/or lag time. Lubricants and glidants can be added to the press coat blend to facilitate compression.

The dosage forms of the present invention may be prepared by any method known to those skilled in the art so long as the desired composition is obtained.

In one embodiment, there is provided a method for manufacturing an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, the method comprising the steps of: (a) obtaining a second active pharmaceutical ingredient comprising from about 1 mg to about 1000 mg a core of an active pharmaceutical ingredient; (b) compressing a powder on the surface of the core to form a sustained release coating on the surface of the core, wherein the powder comprises at least one swellable erodible polymer and a filler; and (c) compressing the A second powder is compressed onto the surface of the sustained release coating, wherein the second powder comprises from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; wherein the immediate release portion comprises the compressed second powder, and the sustained release portion comprises the core and the sustained release portion. release coating.

In another embodiment, there is provided a method for manufacturing an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, the method comprising manufacturing an immediate release portion comprising the first active pharmaceutical ingredient and a second active pharmaceutical ingredient. A dosage form of a sustained release portion of a pharmaceutical ingredient, the method comprising: (a) obtaining a core comprising from about 1 mg to about 1000 mg of a first active pharmaceutical ingredient; (b) compressing a coating on the surface of the core to form a coating on the surface of the core. forming a sustained release coat, wherein the coat comprises at least one swellable erodible polymer and a filler; and (c) compressing the immediate release powder onto the surface of the sustained release coat, wherein the immediate release powder comprises from about 1 mg to about 1000 mg wherein the immediate release part comprises a compressed immediate release powder, and the sustained release part comprises a core and a sustained release coating.

The following examples are provided to further illustrate the compositions and methods of the present invention. It should be understood that the invention is not limited to the examples described.

Examples of press coat blends are shown in the table below. The cores were compressed between 103 and 106 mg, and the coating content was approximately three times (3X) the core weight, for a total tablet weight between 418 and 429 mg.

Example 1

The core used contained ibuprofen, sodium starch glycolate (EXPLOTAB) and fumed silica (Cab-O-Sil).

Table 1: Compression Coating Blend Formulations (% of Formulation)

Table 2: Compression Coating Blend Formulations (% of Formulation)

Table 3: Compression Coating Blend Formulations (% of Formulation)

Example 2

The core used contained ibuprofen, sodium starch glycolate (EXPLOTAB) and fumed silica (Cab-O-Sil).

Part A: Pulse Release Coated Formulation :

(a) Lactose, hydroxypropylmethylcellulose and hydroxypropylcellulose were passed through a #40 mesh screen to de-agglomerate.

(b) De-lumped lactose, hydroxypropylmethylcellulose and hydroxypropylcellulose (a) were mixed in a suitable v-blender at 25 RPM for 15 minutes.

Compression-coated tablets :

(a) Place the desired amount of blend from Table 4 into a compression mold and tamp down at less than 500 pounds per square inch (psi) to form a bottom layer. Add chips.

(b) Additional blend amounts from Table 4 were added on top of the tablets from step (a) and processed on a Carver press (Menomonee Falls, WI) equipped with a 9 mm round, shallow concave die set. Further pressing with a pressing force of 3000lbs. The upper and lower layers of the press-coated portion were presented in a ratio of 1.29:1.

(c) Tested using United States Pharmacopeia (USP) dissolution apparatus #1 (basket) at 100 RPM in dissolution medium 0.1N HCl for 2 hours, followed by phosphate buffer pH 5.6 at 37°C for 3-8 hours Solubility of the press-coated tablets from step (b).

(d) Prepare the tablet set in the same weight ratio (1.29:1 ratio) as in step (a) and step (b), for a total target tablet weight of 424.38 mg, the total compression coat weight 3x times the weight of the core, 139mg in the bottom part and 179mg in the upper part. Three tablets were tested using the same dissolution method as in (c), resulting in a dissolution with less than 1% released ibuprofen by 6.25 hours (e.g., at least 4 hours lag time), at 8 hours Afterwards there was an average dissolution rate of ibuprofen released greater than 80%, with an average dissolution time of 403 minutes (6.71 hours). See Figure 1.

(e) Tablet sets were prepared in the same weight ratio (1.29:1 ratio) as in step (a) and step (b), for a total target tablet weight of 376.38 mg, the total compression coat weight 2.5 times the weight of the core, 118mg in the bottom part and 152mg in the upper part. Three tablets were tested using the same dissolution method as in (c), resulting in a dissolution with less than 1% released ibuprofen before 4.5 hours (e.g., at least 4 hours lag time), at 6 hours Afterwards there was an average dissolution rate of ibuprofen released greater than 80%, with an average dissolution time of 310 minutes (5.17 hours). See Figure 2.

(f) Prepare tablet sets in the same weight ratio (1.29:1 ratio) as in step (a) and step (b), for a total target tablet weight of 318.38 mg, the total compression coat weight 2.0 times the weight of the core, 93 mg in the bottom portion and 119 mg in the upper portion. Three tablets were tested using the same dissolution method, yielding a dissolution with less than 1% released ibuprofen before 3.5 hours (e.g., a lag time of at least 3 hours) and greater than 80% after 5 hours. The average dissolution rate of released ibuprofen, the average dissolution time was 238 minutes (3.96 hours). See Figure 3.

Table 4: Pulse Release Coating Formulations :

Example 3

An additional 208.0 mg of ibuprofen blend, sodium starch glycolate (EXPLOTAB) and fumed silicon dioxide (Cab-O-Sil) was added to the mold containing the press-coated tablet to form an immediate release of the tablet part. Tablets are additionally compressed to form bilayer tablets.

Example 4

Two-chip tablet: 200mg plus 100mg

The cores from Example 2 were used to prepare two-core tablets. A 200mg core of ibuprofen was prepared by compressing 212.8mg of the blend on a rotary press. 418.9 mg of the press-coat blend from Example 2 was placed in a round tablet mold as the bottom layer, and the 200 mg core and the 100 mg core from Example 2 were placed tangentially on top of the press-coat blend. An additional 538.6 mg of the compression coat blend was placed on top of the top layer and the tablets were compressed. A 200 mg core is partially exposed on the tablet surface to provide immediate release, while a 100 mg core provides sustained release.

Example 5

Three-chip tablet: 100mg plus 100mg plus 100mg

Three core tablets were prepared using 100 mg of the core tablet from Example 2. 418.9 mg of the press-coat blend from Example 2 was placed in a round tablet mold as the bottom layer, and three 100 mg core tablets from Example 2 were placed tangentially on top of the press-coat blend. An additional 538.5 mg of the compression coat blend was placed on top and the tablets were compressed. Two of the three 100 mg cores are partially exposed on two opposite side surfaces of the tablet to provide immediate release, while the one core 100 mg tablet provides sustained release in the center of the tablet.

Example 6

Two-chip tablet: 150mg plus 150mg

The cores from Example 2 were used to prepare two-core tablets. The 150 mg ibuprofen cores were prepared by compressing 159.6 mg of the blend per core on a rotary press. 418.9 mg of the press-coat blend from Example 2 was placed in a round tablet mold as the bottom layer and two 150 mg cores were placed tangentially on top of the press-coat blend. An additional 538.5 mg of the compression coat blend was placed on top and the tablets were compressed. One of the two 150 mg cores was partially exposed on the tablet surface to provide immediate release, while the other 150 mg core provided sustained release.

Example 7

Three-chip tablet: 75mg plus 150mg plus 75mg

Three core tablets were prepared using the cores from Example 2. 75 mg ibuprofen cores were prepared by compressing 79.8 mg of the blend per core on a rotary press. The 150 mg ibuprofen cores were prepared by compressing 159.6 mg of the blend per core on a rotary press. 418.9 mg of the press-coat blend from Example 2 was placed in a round tablet mold as the bottom layer and two 75 mg cores were placed tangentially opposite the 150 mg core on top of the press-coat blend on the side. An additional 538.5 mg of the compression coat blend was placed on top and the tablets were compressed. Two 75 mg cores are partially exposed on opposite sides of the tablet surface to provide immediate release, while the 150 mg core is in the center and provides sustained release.

Example 8

Preparation of Wax-Free Press-Coated Tablets (Comparative Example)

The core used contained sodium ibuprofen dihydrate, porous silica and silicon dioxide.

The blends in Table 5 were prepared according to the following method :

(g) Lactose, hydroxypropylmethylcellulose and hydroxypropylcellulose were de-lumped by passing through a #40 mesh screen.

(h) De-lumped lactose, hydroxypropylmethylcellulose and hydroxypropylcellulose (a) Blend in a suitable v-blender at 25 RPM for 15 minutes.

(i) Add silica and blend for an additional 3 minutes.

Table 5: Compression Coating Blends

Preparations (tablets) Coating by core weight 2x Material % of blend Lactose monohydrate (Fast Flo 316) 55.0% Carnauba Wax - Hydroxypropyl Cellulose (Klucel EXF) 30.0% Hydroxypropyl Methyl Cellulose (Methocel K4MCR) 15.0% Silica (Cab-O-Si) - Hydroxypropyl Cellulose (Klucel EXF) - total 100% Delay between initial release and >90% release 2.0 hours

The coatings in Table 5 were compressed using Method A below.

Press Coating - Method A and Method B :

Method A (for 2.6X coating weight: 143 mg x 2.6 = 371.8 mg)

1. Assemble 5/16" round flat beveled edge punch

2. Compress the core tablet (143mg) under a pressure of 0.5 tons

3. Assemble 15/32" round flat beveled edge punch

4. Put 9/16 (209.2mg) of the coating material into the mold cavity

5. Gently place the core tablet from step #2 into the center of the punch on top of the coating material.

6. Place the remaining 7/16 (162.7 mg) of coating material into the cavity on top of the core tablet.

7. Gently flatten the material and press it under 0.75 tons

Method B (for 2.6X coat weight: 143 mg x 2.6 = 371.8 mg

1. Assemble 5/16" round flat beveled edge punch

2. Lightly tamp 20% (74.4mg) of the coating material

3. Add 143mg of core blend

4. Compression of bi-layer tablets at 0.5 tons

5. Assemble the 15/32" round FFBE stamping machine

6. Center the bi-layer tablet from step #4 on the bottom punch and place the remaining 80% (297.4 mg) of coating material on top of the bi-layer tablet

7. Compress the final tablet at 0.75 tons

Example 9

Compression Coating Blends

Part A: Samples using 10% wax

The blends from Table 6 were compressed at various weights using the core tablets from Example 8, and the compression procedure was as follows. The weight of the coating material was varied at 1.8X, 2X, 2.3X and 2.6X of the core tablet weight. In Test 1 (Sample 1), silica was added.

Table 6: Compression Coating Blend Formulations (% of Formulation)

10% Carnauba Wax, 15% HPMCK4MCR, 30% HPCEXF, 45% Lactose

1: Commercially available from Foremost Farms Corporation (Baraboo, WI)

2: Commercially available from Ashland Corporation (Covington, KY)

3: Commercially available from DOW Chemical Company (Midland, MI)

4: In Table 6, the method A (from Example 8) of Trial 4 and the method B (from Example 8) of Trial 1 to Trial 3 were used for compression coating.

Part B: Use 30% wax, HPMCK4MCR/HPCEXF ratio 15%/30% sample

The blends from Table 7 were compressed at various weights using the core tablets from Example 8, and the compression procedure was as follows. The weight of the coating material was compressed to 2.6X the weight of the core tablet. Multiple tablets were compressed with each sample variation.

Table 7: Compression Coating Blend Formulations (% of Formulation), 30% Wax

Preparations (tablets) Test 5 Coating Weight by Core Weight 2.6x Material Lactose monohydrate (Fast Flo 316) 24.5% Carnauba Wax 30.0% Hydroxypropyl Cellulose (Klucel EXF) 30.0% Hydroxypropyl Methyl Cellulose (Methocel K4MCR) 15.0% Silica (Cab-O-Si) 0.5% Hydroxypropyl Cellulose (Klucel EXF) - total 100.0% Delay (hours) 6.0

In Table 7, method B (from Example 8) of Trial 5 was used for compression coating.

Part C: Using 30% wax, the ratio of HPMCK4MCR/HPCEXF is 13%/26% sample

The blends from Table 8 were compressed at various weights using the core tablets from Example 8, and the compression procedure was as follows. The weight of the coating material was compressed to 2.6X the weight of the core tablet. Multiple tablets were compressed with each sample variation.

Table 8: Compression Coating Blend Formulations (% of Formulation), 30% Wax

Preparations (tablets) Test 6 Coating Weight by Core Weight 2.6x Material Lactose monohydrate (Fast Flo 316) 30.0% Carnauba Wax 30.0% Hydroxypropyl Cellulose (Klucel EXF) 26.0% Hydroxypropyl Methyl Cellulose (Methocel K4MCR) 13.0% Silica (Cab-O-Si) 1.0% Hydroxypropyl Cellulose (Klucel EXF) total 100.0% Delay (hours) 4.5–5.67

In Table 8, method B (from Example 8) of Trial 6 was used for compression coating.

Part D: Samples using 60% wax

The blends from Table 9 were compressed at various weights using the core tablets from Example 8, and the compression procedure was as follows. The weight of the coating material was compressed to 2.6X the weight of the core tablet. Multiple tablets were compressed with each sample variation.

Table 9: Compression Coating Blend Formulations (% of Formulation), 60% Wax

60% Wax, 4% HXF, 35% Lactose, 1% Cab-O-Sil

In Table 9, method B (from Example 8) of Trial 7 was used for compression coating.

Example 10

Preparation of compression-coated tablets with wax

The tablet cores used contained phenylephrine hydrochloride, mesoporous silica and silicon dioxide for a core weight of 155.0 mg and a dose of 138.8 mg phenylephrine hydrochloride.

Part A: Blends in Table 10, prepared according to the following method:

(j) Lactose, hydroxypropylmethylcellulose and hydroxypropylcellulose were passed through a #40 mesh screen to de-agglomerate.

(k) De-lumped lactose, hydroxypropylmethylcellulose, hydroxypropylcellulose (a) and carnauba wax were mixed in a suitable v-blender at 25 RPM for 15 minutes.

(1) Add silica and blend for an additional 3 minutes.

Table 10: Compression Coating Blends

Preparations (tablets) Coating by core weight 2x Material % of blend Lactose monohydrate (Fast Flo 316) 30.0% Carnauba Wax 30.0% Hydroxypropyl Cellulose (Klucel EXF) 26.0% Hydroxypropyl Methyl Cellulose (Methocel K4MCR) 13.0% Silica (Cab-O-Si) 1.0% total 100% Delay between initial release and >90% release 2.0 hours

In Table 10, method B (from Example 8) was used for compression coating.

Example 11

Dissolution result

Using the United States Pharmacopeia (USP) Dissolving Apparatus #1 (basket) at 100 RPM, in the dissolution medium 0.1N HCl for 1 hour, followed by 1 hour to 7 hours in phosphate buffer at pH 6.8 to test the samples from Example 8, Example 9. Dissolution of the tablet of Example 10. Test samples for ibuprofen release, compared to a standard of 100% release. Results included the degree of tablet-to-tablet variability.

(a) In the dissolution profile shown in Figure 4, tablets prepared using compression method A (from Example 8) did not show a lag time for ibuprofen release until greater than 2 hours and did not release more than 2 hours until greater than 3.5 hours. 90% ibuprofen. This indicates that this formulation is not suitable for the active ingredient as a pulsatile release.

(b) In the dissolution profile shown in Figure 5, tablets from Example 9, Part A (10% wax) were compressed coated at 1.8X core weight using compression method B (from Example 8) at 2 hours No greater than 10% of the ibuprofen was released at (indicated lag time) and the ibuprofen was not slowly released until 4 hours, indicating that no significant pulse release was shown.

(c) In the dissolution profile shown in Figure 6, from Example 9 using compression method A (from Example 8) at 2X core weight for compression coating, the tablets in Part A (10% wax) had Significant pulse release of greater than 80% ibuprofen beginning between 1 hour and 5.5 hours.

(d) Also, in the dissolution profile shown in Figure 6, the tablets from Example 9, Part A (10% wax) using compression method B (from Example 8) were compressed coated at 2X core weight with Significant pulse release of greater than 80% ibuprofen starting between 3 hours and 5.5 hours.

(e) In the dissolution profile shown in Figure 7, tablets from Example 9, Part A (10% wax) using compression method B (from Example 8) with a compression coating at 2.3X core weight are shown in The release of the variation starts between 3.5 hours and 5.5 hours.

(f) In the dissolution profile shown in Figure 8, the tablets from Example 9, Part A (10% wax) using compression method A (from Example 8) that were compression coated at 2.6X core weight show A variable release started between 4 hours and 6.5 hours, but no apparent pulse release was shown.

(g) In the dissolution profile shown in Figure 9, from Example 9, Part B (30% Wax, 15% HPMCK4MCR, 30% HPCEXF ) shows a sustained release rate of ibuprofen of less than 10% release at 6 hours, followed by a distinct pulse with 90% release at 7 hours.

(h) In the dissolution profile shown in Figure 10, from Example 9, Part C (30% Wax, 13% HPMCK4MCR, 26% HPCEXF ) shows a sustained release rate of ibuprofen with onset release between 4.5 hours and 5 hours, showing a distinct pulse release with greater than 80% release at 6 hours.

(i) In the dissolution profile shown in Figure 11, the tablets from Example 9, Part D (60% wax) were compression coated at 2.6X core weight using compression method B (from Example 8) shown in Release started between 4 hours and 5 hours with >80% release at 6 hours.

(j) In the dissolution profile shown in Figure 12, the tablets from Example 10 (30% wax) that were compression coated at 2.6X core weight showed release starting between 4 hours and 5 hours, at There was greater than 80% release at 6 hours.

Additional tablets were prepared in the same weight ratio, for a total target tablet weight of 372 mg, the total compression coat weight was 2.6x times the core weight, 116 mg in the bottom portion and 150 mg in the upper portion. Three tablets were tested using the same dissolution method as in (c), resulting in a dissolution with less than 2% released ibuprofen after 4 hours (e.g., a lag time of at least 4 hours), after 4 hours With an average dissolution rate of ibuprofen released greater than 80%, the average dissolution time was 310 minutes (5.17 hours).

Example 12

Two-chip tablet: 200mg plus 100mg

The cores from Example 8 were used to prepare double chip tablets. 200 mg ibuprofen cores were prepared by compressing 286 mg of the blend on a rotary press. 223.08 mg of the press-coat blend from Example 8, Part C (Table 5) was placed in a round tablet mold as the bottom layer, and the 200 mg core and the 100 mg core from Example 8 were placed tangentially into the press-coat co-coating. on top of the mixture. An additional 892.32 mg of the compression coat blend was placed on top of the top layer and the tablets were compressed. A 200 mg core is partially exposed on the tablet surface to provide immediate release, while a 100 mg core provides sustained release.

Example 13

Three-chip tablet: 100mg plus 100mg plus 100mg

A three-chip tablet was prepared using 100 mg of the core from Example 8. 223.08 mg of the press-coat blend from Example 8, Part C (Table 5) was placed in a round tablet mold as the bottom layer and three 100 mg core tablets from Example 8 were placed tangentially into the press-coat Blend on top. An additional 892.32 mg of the compression coat blend was placed on top and the tablets were compressed. Two of the three 100 mg cores are partially exposed on two opposite side surfaces of the tablet to provide immediate release, while the one core 100 mg tablet provides sustained release in the center of the tablet.

Example 14

Two-chip tablet: 150mg plus 150mg

The cores from Example 8 were used to prepare double chip tablets. The 150 mg ibuprofen cores were prepared by compressing 214.5 mg of the blend per core on a rotary press. 223.08 mg of the press-coat blend from Example 8 was placed in a round tablet mold as the bottom layer and two 150 mg cores were placed tangentially on top of the press-coat blend. An additional 892.32 mg of the compression coat blend was placed on top and the tablets were compressed. One of the two 150 mg cores was partially exposed on the tablet surface to provide immediate release, while the other 150 mg core provided sustained release.

Example 15

Three-chip tablet: 75mg plus 150mg plus 75mg

Three core tablets were prepared using the cores from Example 8. The 75 mg ibuprofen cores were prepared by compressing 107.25 mg of the blend per core on a rotary press. The 150 mg ibuprofen cores were prepared by compressing 214.5 mg of the blend per core on a rotary press. 223.08 mg of the press coat blend from Example 8 was placed in a round tablet mold as the bottom layer and two 75 mg cores were placed tangentially opposite the 150 mg core on top of the press coat blend on the side. An additional 892.32 mg of the compression coat blend was placed on top and the tablets were compressed. Two 75 mg cores are partially exposed on opposite sides of the tablet surface to provide immediate release, while the 150 mg core is in the center and provides sustained release.

Although the invention has been described above in conjunction with specific embodiments of the invention, it is obvious that various changes, modifications and variations can be made without departing from the inventive concepts disclosed herein. Accordingly, this document is intended to cover all such changes, modifications and variations that come within the true and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are hereby incorporated by reference in their entirety.

Claims (34)

1. A dosage form comprising an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, wherein (a) the immediate release portion comprises from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; and (b ) said extended release portion comprises from about 1 mg to about 1000 mg of a second active pharmaceutical ingredient; wherein said extended release portion is coated with an extended release coating comprising at least one swellable erodible polymer and a filler, and wherein said The immediate release portion is in contact with the sustained release coating. 2. The dosage form of claim 1, wherein the swellable erodible polymer is selected from the group consisting of water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic acid Polymers, hydrocolloids, gelling starches and swellable cross-linked polymers, and their derivatives, copolymers and combinations. 3. The dosage form of claim 1, wherein the swellable erodible polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and mixture. 4. The dosage form of claim 1, wherein the coating comprises two swellable erodable polymers. 5. The dosage form of claim 1, wherein the filler is selected from the group consisting of water insoluble polymers, lactose, dextrose, sucrose, mannose, mannitol, sorbitol, erythritol , xylitol, fats, fatty acid esters, phospholipids, waxes, vegetable oils, free fatty acids and their salts, phospholipids, and mixtures thereof. 6. The dosage form of claim 1, wherein the filler is selected from the group consisting of lactose, carnauba wax, and mixtures thereof. 7. The dosage form of claim 1, further comprising optional ingredients selected from the group consisting of other active substances, lubricants, glidants, sweeteners, colors, Flavoring agents, superdisintegrants, compressible fillers, and mixtures thereof. 8. The dosage form of claim 1, wherein the first active pharmaceutical ingredient in the immediate release portion and the second active pharmaceutical ingredient in the extended release portion are the same. 9. The dosage form of claim 1, wherein the second active pharmaceutical ingredient is released about 4 to about 6 hours after the release of the first active pharmaceutical ingredient. 10. The dosage form of claim 1, wherein the dosage form provides about 10-12 hours of treatment. 11. A dosage form comprising: (a) an immediate release portion comprising about 100 mg to about 400 mg of sodium ibuprofen; (b) an extended release portion comprising from about 50 mg to about 400 mg of sodium ibuprofen; and (c) a coating surrounding said extended release portion, said coating comprising at least one swellable erodible polymer and a filler; and wherein the immediate release portion is in contact with the sustained release coating. 12. The dosage form of claim 11, wherein the swellable erodible polymer is selected from the group consisting of water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic acid Polymeroids, hydrocolloids, clays, gelling starches, and swellable crosslinked polymers, and their derivatives, copolymers, and combinations. 13. The dosage form according to claim 11, wherein the swellable erodible polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and mixture. 14. The dosage form of claim 11, wherein the filler is selected from the group consisting of water insoluble polymers, lactose, dextrose, sucrose, mannose, mannitol, sorbitol, erythritol , xylitol, fats, fatty acid esters, phospholipids, waxes, vegetable oils, free fatty acids and their salts, phospholipids, and mixtures thereof. 15. The dosage form of claim 11, wherein the filler is selected from the group consisting of lactose, carnauba wax, and mixtures thereof. 16. The dosage form of claim 11, wherein the sustained release portion is released about 4 to about 6 hours after the immediate release portion is released. 17. The dosage form of claim 11, wherein the sodium ibuprofen in the immediate release portion is about 200 mg and the sodium ibuprofen in the extended release portion is 100 mg. 18. The dosage form of claim 11, wherein the sodium ibuprofen in the immediate release portion is about 150 mg and the sodium ibuprofen in the extended release portion is 150 mg. 19. The dosage form of claim 11, wherein the ratio of the amount of sodium ibuprofen in the immediate release portion to the amount of sodium ibuprofen in the sustained release portion is from about 2:1 to about 1:1. 20. The dosage form of claim 11, wherein the coating is comprised of at least two swellable, erodable polymers. 21. A method for manufacturing an immediate release portion of a first active pharmaceutical ingredient and a sustained release portion of a second active pharmaceutical ingredient, the method comprising: (a) obtaining a core comprising from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; (b) compressing a powder on the surface of the core to form a sustained release coating on the surface of the core, wherein the powder comprises at least one swellable erodible polymer; and (c) compressing a second powder onto the surface of the sustained release coating, wherein the second powder comprises from about 1 mg to about 1000 mg of the first active pharmaceutical ingredient; wherein the immediate release portion comprises the compressed second powder, and the sustained-release portion comprises the core and the sustained-release coating. 22. The method of claim 21, wherein the core is formed by compressing a first powder comprising about 50 mg to about 200 mg sodium ibuprofen. 23. The method of claim 21 , wherein the sustained release coating is formed by adding a first portion of the powder to a mold cavity; then adding the first portion of the powder to the cavity containing the first portion of the powder. the core; then adding a second portion of the powder to the cavity; and then compressing the first portion of the powder, the core, and the second portion of the powder within the cavity to Form the sustained-release coating on the surface of the 24. The method of claim 21, wherein the dosage form is formed by adding the second powder to a mold cavity; then adding the slow release package comprising the slow release package to the mold cavity containing the second powder. coating the core; and then compressing the second powder and the core including the slow-release coating in the mold cavity to form the dosage form. 25. The method of claim 21 , wherein the dosage form is formed by adding a first portion of the powder to a mold cavity; then adding a compound comprising the buffer to the cavity containing the first portion of the powder. releasing the core of the coating; then adding a second portion of the powder to the mold cavity; and then compressing the first portion of the powder, the core comprising the sustained release coating, within the mold cavity and a second portion of the powder to form the dosage form. 26. The method of claim 21 , wherein the dosage form is adapted to release the ibuprofen in the immediate release portion within the first hour after administration of the dosage form, and is adapted to release the ibuprofen within about 2 hours after administration of the dosage form. The ibuprofen in the extended release portion is released from about 1 hour to about 8 hours. 27. The method of claim 21, wherein the ibuprofen in the immediate release portion comprises sodium ibuprofen. 28. The method of claim 21, wherein the swellable erodible polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose. 29. The method of claim 21, wherein the ratio of the amount of ibuprofen in the immediate release portion to the amount of ibuprofen in the extended release portion is from about 2:1 to about 1:1. 30. The method of claim 21, wherein the immediate release portion comprises about 50 to about 400 mg of ibuprofen. 31. The method of claim 21, wherein the sustained release portion comprises about 50 to about 400 mg of ibuprofen. 32. The method of claim 21, wherein the powder comprises at least 15% by weight of a swellable erodable polymer. 33. The method of claim 21, wherein the powder comprises at least 15% by weight of the first swellable erodable polymer and at least 15% by weight of the second swellable erodible polymer. 34. A dosage form made by the method of claim 21.